Alternative Name

The Black Death

Status

Select Agent; Category A

Lethality

Moderate to High

Risk Factors

Proximity to infected animals and fleas

Infectious Dose

1-10 bacteria, more for aerosol (100-20,000)

Treatment

Antibiotics

Contagious in pneumonic form.

Etymology


The plague was likely called the “Black Death” in the Middle Ages for two reasons. First, in advanced stages of the disease, large patches of skin would darken due to bleeding under the skin. Second, the fingers, toes and nose of a patient may turn black due to necrosis, the death of living tissue.

The Justinian Plague

541-542CE- This plague pandemic began in Northern Africa and spread to Europe and Central and South Asia. 50-60% of the infected population died, with more than 10,000 deaths a day at the peak.

The Black Death, Peak Years

1346-1452CE- Fleas on marmot pelts likely transferred Y. pestis from Asia to Europe via trading routes, where the resulting plague killed roughly one-third of the population. This pandemic continued for many years, finally subsiding in 1720.

The Modern Plague

1855 CE- Global transportation routes spread this pandemic plague from China to the rest of the inhabited world. The first plague cases in the United States were identified in 1900 from a port in San Francisco, California. This is the likely source of the now endemic Y. pestis in the western United States.

Introduction

Plague is a zoonotic disease caused by the gram-negative bacteria Yersinia pestis. It is endemic (naturally occurring) on all continents except for Antarctica and Australia. Humans can be infected in a number of ways: by flea bites, most notably from the oriental rat flea (Xenopsylla cheopis), the human flea (Pulex irritans), or the western United States flea (Oropsylla Montana); through eating infected meat; or through the inhalation of respiratory droplets from infected individuals or animals, including domestic cats. A wide variety of mammals can harbor plague, but rodents (rats, mice, ground squirrels and prairie dogs) are most common. The black rat (Rattus rattus), which lives amongst humans, has been historically implicated in the spread of the plague, the “black death,” in the Middle Ages. Fleas contract Y. pestis when they bite and ingest blood from an infected animal. The bacteria multiply in the flea’s foregut and block the digestive tract, starving the flea. The flea will futilely attempt to feed until it dies of starvation, spreading the bacteria to more animals in the process.
Infected humans develop plague symptoms that can be classified as bubonic, septicemic or pneumonic. Bubonic plague is characterized by bubos (tender, swollen lymph nodes) often located near the groin. Septicemtic plague can be primary or develop after bubonic or pneumonic plague, and is characterized by the presence of bacteria in the blood. Pneumonic plague can also develop secondary to the other types of plague and occurs when Y. pestis infects the lungs. Once in the lungs, Y. pestis is contagious and can spread to others through respiratory droplets, causing primary pneumonic plague.

Why is Yersinia pestis considered an effective bioweapon?

Y. pestis is considered an effective bioweapon for the following reasons. It is readily available in the most parts of the world, can be contagious, and has a low infectious dose. It can be aerosolized (stable for 1 hour) to cause the contagious pneumonic form of plague, which has a high fatality rate (57% fatality with treatment). The Soviet Union produced ton quantities of Y. pestis per year, while actively developing strains resistant to multiple antibiotics.

Virulence Factors: What Makes B. anthracis Deadly?

There are a number of proteins which contribute to the virulence of Y. pestis, mainly through interfering with the immune system. The Yop proteins (Yersina outer proteins) are delivered directly to host cells by a needle-like structure called the “injectisome.” A number of Yop proteins (YopH, YopE. YopT) and a gelatinous envelope (the F1 capsule) prevent phagocytosis, the process of an immune cell engulfing and destroying a pathogen. The YopJ protein prevents the production of inflammatory molecules, causing some immune cells to apoptose, or self-destruct. Another protein, the LcrV (Low calcium response Virulence), also known as just V, regulates Yop protein production and causes some immune cells to release immunosuppressive molecules.

Symptoms:

There are three presentations of plague: bubonic, septicemic, and pneumonic. In a biological warfare scenario, Yersinia pestis could be delivered via contaminated vectors (fleas), causing the bubonic presentation, or more likely via aerosol, causing primary pneumonic plague.
Bubonic plague: The incubation period ranges from 2 to 10 days with an acute onset of malaise, fever, chill and weakness. Up to 24 hours later, one or more lymph nodes become swollen, forming a bubo 1-10cm wide. The buboes are extremely tender and painful, often developing in the groin and sometimes under the arms and on the neck. If untreated, bubonic plague may progress into septicemic form, spreading Y. pestis throughout the bloodstream to the rest of the body, including to the central nervous system where it can cause meningitis, and to the lungs, causing pneumonic plague. The mortality for bubonic plague is ~ 13.5% in the United States.
Pneumonic plague: The incubation period is roughly 2 to 4 days for primary pneumonic plague. The onset is acute, with a high fever, trouble breathing and cough, which may produce watery or bloody sputum. Patients may also have gastrointestinal symptoms. The resulting pneumonia progresses rapidly, resulting in death if untreated. The mortality rate for primary pneumonic plague is 57% in the United States.
Septicemic Plague: Primary septicemic plague is less common and presents without buboes, making it difficult to diagnose. Primary or secondary septicemic plague can present with fever, chills, nausea, abdominal pain and vomiting. In advanced stages, patients can exhibit necrosis (tissue death) in the fingers, toes and nose, disseminated intravascular coagulation, (the formation of blood clots within the blood vessels), and purpura (purple blotches of skin caused by subcutaneous (under the skin) bleeding). Septicemic plague has a mortality rate in the United States of ~ 22% with treatment, and near 100% without treatment.

Treatment

Antibiotics, such as streptomycin and chloramphenicol, are highly effective for all plague presentations if begun early. If antibiotics are given within the first 24 hours after the symptoms of pneumonic plague develop, mortality is significantly reduced. Strict isolation procedures for all cases of plague for 48 hours are indicated after initiation of antibiotic treatment, since Y. pestis can spread from person to person by respiratory droplets.

Vaccination

In 1999, production of the formalin-killed Y. pestis vaccine, Plague Vaccine USP, was stopped. The vaccine was given to US military personnel in the Vietnam War, and it likely did not protect against primary pneumonic plague.
Two new vaccines (based on the F1 capsule and V antigens) are being simultaneously developed by the United States and the United Kingdom. Both are being developed to protect against primary pneumonic plague and are in clinical trials.

References

Dembek, Z.F. [Senior Editor] (2007). Plague, Chapter 5, Medical Aspects of Chemical and Biological Warfare. Publisher: Department of Defense, Office of The Surgeon General, US Army, Borden Institute. 2007: 672 p.; ill http://www.bordeninstitute.army.mil/published_volumes/biological_warfare/biological.html

Inglesby, T.V., et al. (2000). Plague as a Biological Weapon. JAMA, vol 283, No. 17:2281-2290